A "Multiple-Hit" Model of Affective Disorders in Rats Selectively Bred for Differences in Emotional Reactivity: A Novel Animal Model of Treatment-Resistant Depression

Aydin C, Frohmader K, Medina A, Blandino P, Watson S, Akil H
Annual Meeting of the American College of Neuropsychopharmacology. 2015.


Background: Depression is a debilitating disease that renders millions of people in need of life-long treatments. Moreover, approximately two-thirds of patients with depression do not respond to the current pharmacological treatments adequately, and are considered 'treatment-resistant'. To better understand the neurobiological underpinnings of response versus resistance to antidepressants, we aimed to create an animal model of treatment-resistant depression. In doing so, we developed a multiple-hit model, and used selectively bred rats (bLRs, bHRs) from our colony that display innate differences in stress reactivity. Namely, compared to bLRs, bHRs display higher novelty-induced locomotion, and lower anxiety- and depression-like behaviors, and we have shown that these lines exhibit stable, predictable and profound differences in multiple facets of affective behavior, indicating a pervasive difference in emotionality. Using this animal model and the multiple-hit paradigm, we investigated how environmental interventions and differences in genetic background interact to alter affective behavior, and lead to treatment-resistant depression in a subset of vulnerable individuals. In the present study, treatment-resistance was identified by lack of response to a classical antidepressant, fluoxetine (FLX) in bLRHRs that display signs of depressed-like behavior following multiple-hits. Subsequently, efficacy of a novel antidepressant drug in reversing signs of depression-like behavior was assessed in this novel rat model of treatment-resistant depression.

Methods: Forty-third, 44th, and 45th generation male, bred LR and HR rats were obtained from our breeding colony. The multiple-hit paradigm consisted of chronic variable stress (CVS) exposure during adolescence, followed by additional "hits" in adulthood. Control animals were left untouched during this period. Following the last hit, rats in each group were further divided into vehicle (VEH), FLX, or L-acetylcarnitine (LAC) injection groups. After 2 weeks of daily VEH or drug injections, animals received a 15-min stress challenge and got tested on the social interaction (SI) test for assessment of social withdrawal. Following SI testing, rats were euthanized via rapid decapitation and brains were collected. Ongoing studies are assessing the transcriptome profile via RNA seq. in the hippocampi of treatment-resistant versus –responsive bLRHRs with or without a history of multiple-hits.

Results: Our results showed that adolescent CVS exposure affected bLRs and bHRs in opposite ways; inducing resilience in bLRs and vulnerability in bHRs to a stress challenge in adulthood. Moreover, following multiple-hits while bLRs did not behave different than controls, bHRs showed significantly increased social withdrawal compared to their respective controls. This confirmed that environmental challenges encountered in adolescence differentially interact with genetic background to alter affective behavior later in life. Interestingly, our data showed that genetic background determined antidepressant-response as well; while chronic treatment with FLX resulted in increased social interaction time following a stress challenge in bLRs, the identical treatment was ineffective in bHRs. Most importantly, FLX was ineffective in reversing the increased social withdrawal observed in bHRs following multiple hits, indicating treatment resistance in this phenotype. Similar to FLX; a novel antidepressant, LAC, was ineffective in reversing stress-induced social withdrawal in bHRs. Ongoing studies will reveal the transcriptome profile in the hippocampus of treatment-resistant versus –responsive bLRHRs with or without a history of multiple-hits. Additional ongoing experiments are investigating the effectiveness of tricyclic, as well as novel antidepressants in reversing signs of depressed-like behavior in this novel animal model.

Conclusions: Overall, the present data demonstrate the effectiveness of the bLRHR phenoty